Insulin‐like signalling in neurons controls lifespan in C. elegans

Insulin‐like signalling controls C. elegans lifespan, development and metabolism. Mutations that weaken this insulin‐like signalling pathway extend lifespan. Severe mutations abolishing insulin‐like signalling cause animals to arrest development as dauer larvae, a larval form specialized for stress resistance and long‐term survival. A number of the genes acting in this pathway have been cloned, including daf‐2, which encodes a homolog of vertebrate insulin/IGF‐I receptors, and age‐1, encoding the C. elegans homolog of the PI(3)K p110 catalytic subunit. In order to identify cells from which insulin‐like signalling controls lifespan and development, transgenic animals were constructed which possessed insulin‐like signalling only in specific cell types. To achieve this, cell‐type specific promoters were used to drive expression of daf‐2 or age‐1 cDNAs in daf‐2(–/–) or age‐1(–/–) backgrounds, respectively. By utilizing this strategy, we could restore wild‐type daf‐2 or age‐1 activity only in cells that are capable of expressing each transgene. Restoring insulin‐like signalling to the nervous system of daf‐2 or age‐1 mutants could rescue long lifespan. This result was specific for transgenes restoring insulin‐like signalling to the nervous system. Expressing daf‐2 or age‐1 cDNAs from muscle‐ or intestinally‐restricted promoters was insufficient to rescue lifespan. In contrast, age‐1 and daf‐2 expression in either neuronal or non‐neuronal cell types rescued dauer larval arrest in the mutants. These findings demonstrate that insulin‐like signalling pathways in the nervous system control C. elegans lifespan.